Novel 2-oxa-steroids

ABSTRACT

2 - OXA - 13B - R-17A-METHYL-$4,9,11-GONATRIENES OF THE FORMULA   3-(O=),17-(R&#39;&#39;-O-),17-CH3-ESTRA-4,9,11-TRIENE WHERE C2   IS O AND C18 IS R   WHEREIN R IS SELECTED FROM THE GROUP CONSISTING OF METHYL AND ETHYL AND R&#39;&#39; IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, SATURATED ALKYL OF 1 TO 5 CARBON ATOMS WHICH MAY CONTAIN A HETERO OXYGEN ATOM, UNSATURATED ALKYL OF 2 TO 5 CARBON ATOMS, CYCLOALKYL OF 3 TO 5 CARBON ATOMS WHICH MAY CONTAIN A HETERO OXYGEN ATOM, WITH THE PROVISO THAT R IS ETHYL WHEN R&#39;&#39; IS HYDROGEN WHICH COMPOUNDS POSSESS ANABOLIC AND ANDROGENIC ACTIVITY. THE INVENTION ALSO RELATES TO A NOVEL PROCESS AND NOVEL INTERMEDIATES FOR THE PREPARATION OF THE COMPOUNDS OF FORMULA I.

United States Patent 3,752,855 NOVEL Z-OXA-STEROIDS Robert Bucourt andLucien Nedelec, Clichy-sous-Bois, France, assignors to Roussel UCLAF,Paris, France No Drawing. Original application Aug. 14, 1968, Ser. No.752,467, now Patent No. 3,595,877. Divided and this application Feb. 3,1971, Ser. No. 112,408 Claims priority, application France, Aug. 17,1967, 118,090, 118,091; Dec. 7, 1967, 131,343; Mar. 7,

Int. Cl. C07c 49/00 vs. Cl. 260-586 H 3 Claims ABSTRACT OF THEDISCLOSURE 2 oxa 13B R-l7a-methyl-A '"-gonatrienes of the formula 1 0 vwherein R is selected from the group'consisting of methyl and ethyl andR is selected from the'group consisting of hydrogen, saturated alkyl of1 to 5 carbon atoms which may contain a hetero oxygen atom, unsaturatedalkyl of 2 to 5 carbon atoms, cycloalkyl of 3 to 5 carbonatoms which maycontain a hetero oxygen atom, with the proviso that R is ethyl when R ishydrogen which compounds possess anabolic and androgenic activity. Theinvention also relates to a novel process and novel intermediates forthe preparation of the compounds of Formula I.

PRIOR APPLICATION This application is a division of our copending US.

application Ser. No. 752,467, filed Aug. 14, 1968, now' US. Pat. No.3,595,877.

OBJECTS OF THE INVENTION The novel products of the invention are2-oxa-17umethyl-A -gonatrienes oi the formula v wherein R is selectedfrom the group consisting of methyl and ethyl and R is selected from thegroup consisting of hydrogen, saturated alkyl of Ito 5 carbonatoms whichmay contain a hetero oxygen atom, unsaturated 3,752,855 Patented Aug.14, 1973 alkyl of 2 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atomswhich may contain a hetero oxygen atom, with the proviso that R is ethylwhen R is hydrogen. Two preferred compounds of Formula :I are 2-oxa-17a-methyl-17fl (Zg-tetrahydropyranyl)-oxy-A estratriene 3 one and 2oxa 13B-ethyl-17a-methyl- A -gonatriene-l7fi-ol-3-one.

The novel process of the invention .for the preparation of 2 oxa 17ozmethyl-A -gonatrienes of Formula I comprises oxidizing 13/8-R-des A-A-gonaene-17fi-ol-5- one where R has the above definition to form 133-R-des A-A -gonaene-5,17-dione, reacting the latter with a secondaryamine of the formula wherein R and R are alkyl of 1 to 6 carbon atomsand together with the nitrogen atom to which they are attached form asubstituted or unsubstituted heterocyclic ring which may contain anadditional nitrogen or oxygen hetero atom to form the corresponding5-enamino-13B-R- des A-A -gonadiene-17-one, reacting the latter with amethylating agent to form the corresponding 5- enamino-l3fl-R-l7a-methyldes A-A -gonadiene- 17 8-01, reacting the latter with acetoformic mixedanhydride to form 10-hydroxymethylene-1Sfi-R-17a-methyl-des A-A-gonaene-17B-ol-5-one, dehydrogenating the latter with a substitutedp-benzoquinonc to form the corresponding IO-formyl-l3p-R-l7a-methyl-desA-A -gonadiene- 17B-ol-5-one, reducing the latter with an alkali metalborohydride to form the corresponding IO-hydroxymeth'yl- 13B R 17amethyl-des A-A -gonadiene-17B-0l-5-one, reacting the latter withdihydropyran to form IO-tetrahydropyranyloxymethyl-l3B-R-17a-methyl 17,3tetrahydropyranyloxy-des A-A -gonadiene-5-one, subjecting the latter tothe Reformatzky reaction with ethyl bromoacetate to form5-carbethoxymethyl IO-tetrahydropyranyloxymethyl-l3B-R-17a-methyl 17,8tetrahydropyranyloxy-des A-A -gonadiene-5-ol and subjecting the latterto acid treatment to form 2-oxa-13 9-R-17u-methyl-Agonatriene-l7fi-ol-3-one which may be etherified in the 17fl-hydroxylposition. The reaction is illustrated in the following flow sheet.

wherein R, R, R and R have the above definitions.

Among the preferred process modifications are the use of sulfo-chromicacid in acetone as the oxidizing agent and the secondary amine isdiethyl amine, pyrrolidine, piperidine and morpholine. The methylatingagent may be methyl lithium or methyl magnesium bromide, chloride oriodide.

Suitable p-benzoquinones are dihalo-dicyano-p-benzo quinone such as2,3-dicyano-5,6-dichloro-p-benzoquinone. The tetrahydropyranyl ethersmay be formed in ether in the presence of an acid catalyst such asp-toluene sulfonic, acid. The Reformatsky reaction is preferablyeffected in a mixture of dimethoxymethane and tetrahydrofuran and theacid treatment is preferably efiected with a mixture hydrochloric acidand acetic acid.

The compounds of Formula I have a high anabolic and androgenic activityin animals greater than known 2-oxa- 13B-R-A -gonatrienes. In animalstheir superiority is several times that of other trienic or2-oxa-steroids and is manifested on the genital organs and on themuscles.

However, clinical data in human therapy has shown that these compoundslack noticeable elfects on the genital organs at the doses used.Moreover, administration at the very weak doses used, while bringingabout a rapid and considerable increase in Weight, does not bring anyincrease in the content of seral transaminases. The advantage of thesecompounds thus rests in the fact that it is possible to find very weakdoses already definitely active and nevertheless not manifesting anyhepatic toxicity. The clinical studies in human therapy have shown thatthese products can be administered in a discontinuous manner as a resultof a prolonged effect on the anabolism. In other words, the saidcompounds of the invention are useful for the treatment of disturbancesof protein anabolism, asthenia, wastings, osteoporosis, andropause,senescence, delays in the mending of fractures, metabolicdisturbances-"of prolonged corticothe'rapy, adiposogenital syndrome,functional menometrorrhagias, fibromas, endometriosis, and as scarringagents for sores or varicose ulcers. 1 1' The anabolic compositions ofthe invention are comprised of an effective amount of at least one2-oxa-13fi- R-17a-methyl-A -gonatriene of Formula I and a major amountof a pharmaceutical carrier. The compositions may be in the form ofdrinkable or injectable solutions or suspensions, implants, tablets,coated tablets, soft capsules,

swblingual tablets, capsules, granules, emulsions, suppositories,syrups, ointments, creams and topical powders pre pared in the usualmannerQThe usual effective individual dose is 0.2 to 5.0 mg. per day inthe adult.

The novel method of inducing anabolic activity in warm-blooded animalsand humans comprises administering to said animals or humans aneffective amount of at least one 2-oxa-l3 9-R-17a-methyl-A -gonatrieneof Formula I. The said compounds may be administered orally,perlingually, transcutaneously, rectally or topically on skin or mucosa.The usual useful daily dosage is 5 pg. to 85 ,ug./kg. depending'upon themethod of administration and the specific compound.

In the following examples there are described several preferredembodiments to illustratethe invention. However, it should be understoodthatthe invention is not intended to be limited to the specificembodiments.

EXAMPLE I Preparation of2-oxa-17a-methy1-17fi-(Z'Hetrahydropyranly)-oxy-A l-estratriene-3 -oneform, slightly soluble alcohol and insoluble in water..

Infra-redspectmm (chloroform): Presence of enamine at 1622 cm:- and 1593cm:-

I Ultraviolet spectrum'(ethe r): max. at 281 mp, e=25,400

Step B: 5-pyrrolidyl-17a-methyl-des A-A estradiene 17fl-ol.A solution of116 gm. of 5 pyrrolidyl-des A-A -estradiene 17 one in 560 cc. .oftetrahydrofuran was added to 2.45

liters of 1.22 N ethereal solution of methyl lithium at 0, +5 C. and themixture was then agitated for three hours at that temperature. Then thereaction mixture was poured into a solution of water, ice and NH Cl andthe mixture was extracted with ethyl ether. The extracts were combined,washed with water, added to 2 liters of methyl- 118 C. The productoccurred in the form of a solid:

orange-yellow product, soluble in alcohol, acetone, benzene andchloroform, slightly soluble in ether and insoluble in water.

Infrared spectrum (chloroform) Presence of conjugated O=C at 1626 cm."and 1598 cmr As far as is known, this compound is not described in' vthe literature.

Step C: 10-hydroxymethylene-17a-methy1-des A-Aestraene-17fl-ol-5-one.-l12 -cc. of triethylamine were added to asolution of 117 gm. of the pyrrolidyl enamine of Step B in 1170 cc. oftetrahydro'furan and after adiusting the temperature to 10 C., 285 cc.of mixed formic-acetic acid anhydride obtained from sodium formate andacetyl chloride were added thereto. The mixture was agitated for 15minutes, then maintained .at 0). C. for one hour and then at 10} C. forone ho'ur- 465,.

\ "cc. of water were then added tothe mixture and the I temperature wasraised 'to'roomj temperature. Afterbeing I 5 agitated overnight, themixture was poured into a water: ice mixture and extracted with ether.The ether phase was washed with water and then with ice-cooled aqueoussolution of 5% sodium bicarbonate. The ether phase was then extractedwith 0.5 N sodium hydroxide and after the addition of 1400 cc. of icecooled 2 N hydrochloric acid to the alkaline phase, the precipitateformed was dissolved in ether. The ether was washed with ice cooledwater, with ice-cooled aqueous solution of 2% sodium bicarbonate andthen with water, 2 liters of methylene chloride were added to the etherphase and the organic phase was driedover sodium sulfate and evaporatedto dryness in vacuo to obtain 55.8 .gm. of crudeIO-hydroxymethylene-lh-methyl-des A-A l -estraene-l7B-o1-5-one which isused as such for the next step.

The product occurred in the form of an orange-yellow amorphous product,soluble in dilute aqueous alkalis, alcohol, ether, acetone,-benzene andchloroform and insoluble in water.

Ultra-violet spectrum (1) Ethanol v A max. at 233 In (2) Ethanol-N/ 10'caustic soda Amax. at 231 m As far as is known, this compound is notdescribed in the literature.

Step D: tl-formyl-17a-methyl-des A-A -estradiene- 17/3-ol-5-one.--55.80gm. of IO-hydroxymeth'ylene compound prepared in Step C we're'dissolvedin 560 cc. of dioxane and after cooling the resulting solution to 10 C.,a solution of 53.5 gm. of 2,3-dichloro-5,'6-dicyano-p-benzoq-uinone in550 cc .of dioxane was added thereto. The mixture was held for 45minutes at 12 C. and then was filtered. The precipitate was washed withether. The organic phases were poured into a water-ice mixture and themixture was decanted. The mixture was extracted with methylene chlorideand 3 liters of ether were added to the organic extract. The organicphase was washed with ice-cooled aqueous solution of 5% sodiumbicarbonate and 1% sodium bisulfite, then with ice-cooled 0.5 N sodiumhydroxide and then with ice-cooled water until the wash waters wereneutral. The organic phase was then dried over sodium sulfate andevaporated to dryness in vacuo to obtain20.3 gm. of crude product. Thecrude product was purified by chromatography on silica gel with elutionwith 4:6 benzene-ethyl acetate mixture and recrystallization fromisopropyl ether containing isopropanol to obtain 5.094 gm. of10-formyl-17a-methyldes A-A -estradiene17fl-o1-5-one having a meltingpoint of 139 C.

The product occurred in the form of soluble in acetone, benzene andchloroform, slightly soluble in ether and insoluble in water.

Analysis.--C H O (molecular weight=260.32): Calculated (percent); C,73.82; H, 7.74. Found (percent): C, 73.8; H, 7.9. v

Infra-red spectrum (chloroform) Presence of OH at 3640 cm.-

Presence of CHO at 2760 cmr and 1695 cm.- Presence of 0:0 at 1665 cm.-

Presence of C=C at 1590 cm.- and 1540 cm.

yellow prisms Ultraviolet spectrum (dioxane) A max. at 230 mn As far asis known, this compound is not described in the literature.

Sept E: 10 hydroxymethyl 17a-methyl-des- A-A estradiene-l7;3-ol-5-one.3.05 gm. of 10-formyl-17ocmethyl-des A-A -estradiene-17fi-ol-5-one weredissolved in 30 cc. of dioxane and 3 cc. of water and after cooling thesolution to 5 C., mg. of sodium borohydride were added thereto. Themixture was agitated at 8 C. for 30 minutes and was then poured into anaqueous solution of 20% sodium chloride. The aqueous phase was extractedwith methylene chloride and the organic phase was washed with wateruntil neutral, dried over sodium sulfate and evaporated to dryness invacuo to obtain 3.08 gm. of crude product. The product was purified bychromatography on silica gel with elution with a 5:95 benzeneethylacetate mixture to obtain 2.65 gm. (66% yield) of 10 hydroxymethyl17a-methyl-des A-A -estradienel7fi-ol-5-one which was used as such forthe next step.

Ultraviolet spectrum (ethanol): max. at 289-290 mg,

As far as is known, this compound is not described in the literature.

Step F: 10 tetrahydropyranyloxymethyl 17u-methyl- 17Btetrahydropyranyloxy des A-A -estradiene-5- one-7.3 gm. of 10hydroxymethyl-17a-methyl-des A- A -estradiene-17/3-ol-5-one, 7.3 cc. ofdihydropyran and 220 mg. of p-toluene sulfonic acid in 370 cc. of etherwere mixed and the mixture was stirred for 7% hours at room temperatureunder nitrogen. After adding 7.3 cc. of dihydropyran thereto, thereaction was allowed to continue for a total time of 30 hours. Thereaction mixture was poured into an aqueous solution of 5% sodiumbicarbonate, was decanted and the aqueous phase was extracted withmethylene chloride. The organic phases were combined, washed with wateruntil neutral, dried over sodium sulfate, filtered and evaporated todryness in vacuo to obtain 12.4 gm. of10-tetrahydropyranyloxymethyl-17amethyl 17fl-tetrahydropyranyloxy-desA-A -estradiene- 5-one which was used as is for the next step.

For analysis, the product was purified by chromatography on silica gelwith elution with 80:20:0.1 mixture of benzene-ethylacetate-triethylamine.

Ultraviolet spectrum (ethanol): A max. at 289 mu,

As far as is known, this compound is not described 'in the literature.

Step G: 2-oxa-17u-methyl-A -estratriene-17fl-ol-3- one.12.4 gm. oflO-tetrahydropyranyloxymethyl-17amethyl 17fl-tetrahydropyranyloxy-desA-A -estradiene- 5-one, 11 gm. of zinc and mg. of iodine were introducedunder nitrogen into 180 cc. of benzeneand one third of a solution of 6.2cc. of ethyl bromoacetate in 15 cc. of benzene was added to the reactionmixture which was then heated atreflux for 10 minutes.,Then the rest ofthe solution of ethyl bromoacetate was added and reflux was continuedfor 20 minutes after which themixture was cooled and filtered. Thefiltrate was washed with benzene and the combined benzene solutions werepoured into a mixture of ice and 2 N hydrochloric acid. The organicphase was decanted off and the aqueous phase. was extracted withmethylene chloride. The combined organic phases were washed with wateruntil neutral, dried over sodium sulfate, evaporated to dryness in vacuoto obtain 15.4 gm. of crude product. Chromatography on silica gel andelution with a 2: 8 ethyl acetate-benzene mixture gave 8 gm. of 5%-carbethoxymethyl-IO-tetrahydropyranyloxymethyl 17a methyl l'lp-tetrahydropyranyloxy-des-A-A -estradine-SE-ol.

Infrared spectrum (chloroform) Presence of associated OH at 3455 cm.Presence of carbonyl at 1720-1708 cm." Band at 1617 cm."

Ultraviolet spectrum (ethanol) A max. at 247 mu, e=22,400 Infl. at about290 m As far as is known, this compound is not described in theliterature.

5.6 gm. of this said 55-carbethoxymethyl derivative were then dissolvedin 140 cc. of methanol at room temperature under a nitrogen atmosphereand after cooling the solution to C., 14 cc. of hydrochloric acid wereadded thereto. The mixture was stirred for 1 hour at 0, C. and then for64 hours at room temperature after which the mixture was poured intowater. The mixture was extracted with methylene chloride and thecombined organic phases were washed with aqueous sodium bicarbonatesolution, then with water until neutral, dried over sodium sulfate andevaporated to dryness in vacuo to obtain 3.295 gm. of crude product.Recrystallization from ether and than 1:1 ethyl acetate-ether mixturegas 1.34 gm. of 2 oxa 17amethyl-A -estratriene-l7 8-ol-3-one having amelting point of 148 C. and a specific rotation [a] =-41:1 (c.==0.5% inchloroform).

The product occurred in the form of colorless needles soluble inalcohol, methylene chloride and ethyl acetate, and insoluble in water.

Analysis.-C H O (molecular weight=286.36): Calculated (percent): C,75.49; H, 7.75. Found (percent): C, 75.6; H, 7.7.

IR spectrum (chloroform) Presence of OH at 3600 cm.- Presence of 0:0 at1593 cm? and 1562 cm." Presence of complex carbonyl at 1710-1690 cm.-

UV spectrum (ethanol) max. at 230 mu Etta-205 A max. at 327-328 m StepH: 2-oxa-Not-methyl-l7 3-(2'g-tetrahydropyranyl) oxy-A-estratriene-3-one.0.3 gm. of 2 oxa 17amethyl-A-estratriene-l7fl-ol-3-one was added to a mixture of 0.5 cc. ofdihydropyran, 12 mg. of p-toluenesulfonic acid and 5 cc. of ether andthe suspension was stirred under nitrogen in the dark during whichdissolution rapidly occurred. After stirring for 2 /2 hours, 0.5 cc. ofdihydropyran was added and stirring continued and then 0.5 cc. ofdihydropyran was again added. After stirring for 6 hours, the solutionwas neutralized by the addition of sodium bicarbonate followed by theaddition of 2 cc. of water. The mixture was extracted with ether and theether phase was decanted off and washed with water, dried over sodiumsulfate and evaporated to dryness in vacuo. The crude residue waspurified by double chromatography on silica gel with elution withbenzene-ethyl acetate. By evaporation of the solvent, 0.278 gm. of2-oxa-17u-methyl-17p-(2.5- tetrahydropyranyl)-oxy-A -estratriene-3-onespontaneously crystallized.

For analysis, the product was recrystallized by dissolution in 1 cc. ofether followed by addition of 1 cc. of isopropyl ether. The solution wasplaced overnight in a refrigerator and then filtered. The precipitatewas washed with isopropyl ether and dried to obtain the product having amelting point of 125 C. and a specific rotation [a] -=-22:2 (c.-='0.6%in chloroform). The product occurred in the form of pale yellow crystalssoluble in alcohol, benzene, chloroform and ether, fairly soluble inolive oil and insoluble in water.

Analysis.C H O (molecular weight=370.50): Calculated (percent): C,74.56; H, 8.16. Found (percent): C, 74.6; H, 8.1.

UV spectrum (ethanol) X max.

230-231 mp, e=6,065 326-427 ma, e=27,900

IR spectrum (chloroform) presence of trienic lactone presence of the COCgroup absence of hydroxyl 2-oxa-l7a-methyl 17p(25-tetrahydropyranyl)-oxy- A -estratriene-3-one, as far as is known, isnot described in the literature.

EXAMPLE II Preparation of 2-oxa-13,3-ethyl-17a-methyl-Agonatriene-17/3-ol-3-one Step A: 13B-ethyl-des-A-M-gonaene 5,17 dione.--25.04 gm. of 13/3 -ethyl-des-A A gonaene-17B-ol-5-one having a meltingpoint of 153 C. (described in French Pat. No. 1,526,963) were dissolvedin 370 cc. of acetone at room temperature and after cooling the solutionto 5 C., 50 cc. of sulfochromic solution was added thereto over an hourwhile constantly keeping the temperature at about 5 C. The mixture wasstirred for 30 minutes at this temperature after which water was addedand the solution stood at room temperature for 30 minutes. The reactionmixture was extracted with methylene chloride and the extracts were 1washed with water, dried, and evaporated to dryness in vacuo. Theresidue was recrystallized from a mixture of isopropyl ether and ethylether to obtain 20 gm. (80% yield) of 13,3-ethyl-des A-Agonaene-5,17-dione having a melting point of 108 C. and a specificrotation [a] =!+25 (c.:=0.6% in chloroform). The .product occurred ascolorless crystals soluble in chloroform, ether, methanol and ethanol.

Analysis.-C H O (molecular weight-=232.3l): Calculated (percent): C,77.55; H, 8.68. Found (percent): C, 77.3; H, 8.8.

As far as is known, this product is not described in the literature.

Step B: -5 pyrrolidyl 13,3 ethyl des A-A gonadiene l7 one.-15.55 gm. ofl3p-ethyl-des A-A gonaene-5,17-dione were dissolved in 150 cc. methanolunder a nitrogen atmosphere and after heating the solution to 50 C., amixture of 6 cc. of pyrrolidine and 6 cc. of methanol was added dropwisein 20 minutes. The reaction mixture was held at 50 C. for another 15minutes and then distilled to dryness in vacuo to obtain S-pyrrolidyl-ISB-ethyl-des A-A -gonadiene-l7-one which is used as such for the nextstep.

As far as is known, this compound is not described in the literature.

Step C: 5-pyrrolidyl-13B ethyl 17a methyl-des A- A -gonadiene17B-ol.-TheS-pyrrolidyl from Step B was dissolved in 100 cc. of tetrahydrofuran and420 cc. of 2 N methyl lithium ethereal solution were added dropwise over30 minutes under a nitrogen atmosphere at an i internal temperature of10 C. The solution was then Step D: 13fl-ethyl-17a-methyl-des A-A-gonaene-17pol-5-one.--The l7a-methyl product of Step C was dissolved in30 cc. of acetic acid and 200 cc. of water were added to the solutionwhich was stirred overnight at room temperature. Then, the reactionmixture was made alkaline by the addition of 2 N sodium hydroxide andthe mixture was extracted with methylene chloride. The extracts werewashed with water, with hydrochloric acid, then with Water, was filteredand evaporated to dryness in vacuo. The=residue was purified bychromatography on magnesium silicate and elution with ether to obtain7.5 gm. of 13,B-ethyl 17a methyl-des A-A -gonaene-17 8-ol-5-one having amelting point of 127-128 C. and a specific rotation of [a] =-88(c.:='0.5% in chloroform). The colorless product was soluble in ether,alcohol, chloroform and acetone.

Analysis. C H O (molecular weight=248.35): Calculated (percent): C,77.37; H, 9.74. Found (percent): C, 77.1; H, 9.9.-

"'As far as is known, this compound is not described in the literature.

Step E: 5-pyrrolidyl-13fi-e hy -17a-methyl-des A-A -gonadiene17B-ol.--The product of Step D was dissolved in 75 cc. of methanol undera nitrogen atmosphere and after heating to 50 C., 3 cc. of pyrrolidinediluted with '3 cc. of methanol was slowly added over 15 minutes. Thereaction mixture was stirred at 50 C. for 40 minutes and then evaporatedto a smallrvolume and ice-cooled and filtered. The precipitate waswashed with methanol, with petroleum ether and dried to obtain 7.6 gm.of S-pyrrolidyLl3fi-ethyl-l7armethyl-des A-A -gonadiene-17B-ol appearingas pale yellow flakes not very stable in air.

Step F; l-hydroxymethylenee13B-ethyl-17a-methyl-des A-A-gonaene-17fl-ol-5-one.The product of Step E was dissolved in a mixtureof 46 cc. of anhydrous dioxane, 23 cc. of anhydrous tetrahydrofuran and3.2 cc. of triethylamine and after cooling the mixture to C., 8.5 cc. ofacetoformic acids anhydride was added and the mixture stirred for 3 /2hours at this temperature. After adding 25 cc. of water to the reactionmixture, the mixture was stirred at room temperature overnight, thenpoured into ice water and extracted with ether. The ether phase waswashed with water and then extracted with a mixture of ice and sodiumhydroxide. The alkaline phases were combined, acidified withconcentrated hydrochloric acid and extracted with methylenechloride. Themethylene chloride extract was dried and distilled to dryn'essto obtain4.7 gm. of 1'0-hydroxymethylene-13p-ethyll7u-methyl-des A-A-gonaene-17fi-ol-5-one in the form of an oil which was used as is forthe next step.

As far as is known, this compound is not described in the literature. I

Step-G: 10-formyl-13B-ethyl-17a-methyl-des A-Agonadiene-17[3-ol-5-one.4.7 gm. of IO-hydroxyethylene- 13,6ethyl-lh-methyl-des A-A -gonaene-l7 )3-01-5-0ne were dissolved in amixture of 23 cc. of anhydrous dioxane, and 23 cc. of anhydrous etherand after cooling the solution to 10 C., 3.4 gm. of2,3-dichloro-5,6-dicyano-p-benzoquinone in 34 cc. of dioxane was slowlyadded thereto. The reaction mixture Was stirred for 1 /2 hour at roomtemperature and then poured into a mixture Step H:10-hydroxymethyl-13,9-ethy1-17a-methyldes A-A-gonadiene-17fi-ol-5-one.--The product of Step G was dissolved in 16 cc.of dioxane and after the addition of 1.6 cc. of water, the reactionmixture was cooled slightly and 69 mg. of sodium borohydride were addedthereto. The reaction mixture was stirred for 1 hour at 6 C. and thenpoured into a mixture of ice and water and extracted with methylenechloride. The extracts were washed with water, dried over sodium sulfateand evaporated to dryness. The residue was chromatographed on aluminaand eluted with methylene chloride containing 2% methanol to obtain 1.2gm. of IO-hydroxymethyl- 13B-ethyl-17a-methyl-des A-A-gonadiene-17B-o1-5-one in the form of a pale yellow oil which was usedas such.

As far as is known, this compound is not described in the literature.

(a) 1.2 gm. of 10 hydroxymethyl 13B ethyl-17amethyl-des A-A-gonadiene-17fi-ol-5-one was dissolved in 60 cc. of anhydrous ether and1.2 cc. of dihydropyran and 36 mg. of p-toluene sulfonic acid were addedthereto. The mixture was stirred at room temperature for 7 hours andafter the addition of 1.2 cc. of dihydropyran, stirring was continuedfor another 16 hours. The mixture was then poured into water andextracted with methylene chloride. The extracts were washed with anaqueous sodium bicarbonate solution, with water, dried over sodiumsulfate and evaporated to dryness to obtain 2 gm. of 10tetrahydropyranyloxymethyl 13B ethyl-17x-methyl-17B-tetrahydropyranyloxy-des A-A -gonadiene-5-one.

(b) 2 gm. of the said tetrahydropyranyloxy compound were dissolved in 24cc. of anhydrous tetrahydrofuran and after adding 24 cc. of 0.86 mole ofthe zinc derivative of ethyl bromoacetate in dimethoxymethane thereto,the reaction mixture was heated to reflux for three hours. Aftercooling, the mixture was poured into ice Water and acidified with 2 Nhydrochloric acid. The mixture was extracted with methylene chloride andthe extracts were dried over sodium sulfate and distilled to dryness toobtain an oil residue which is S-carbethoxymethyl-IO-tetrahydropyranyloxymethyl 13Bethyl-17a-methyl-17fitetrahydropyranyloxy-dcs A-A -gonadiene 5 01 whichwas used as is for the next step.

(c) The said S-carbethoxymethyl derivative was dissolved in 12 cc. ofacetic acid and 1.2 cc. of 2 N hydrochloric acid and the solution wasallowed to stand at room temperature for 40 hours. The reaction mixturewas poured into a mixture of ice and water and was then extracted withmethylene chloride. The organic extracts were washed with water, with asodium bicarbonate solution, then with water, dried and evaporated todryness. The residue was crystallized from benzene to obtain 450 mg. of2-oxa-13B-ethyl-17a-methyl-A -gonatriene-175-01-3- one having a meltingpoint of first C. and then 162 C.

The mother waters were distilled and the residue was chromatographed onalumina with elution with benzene and then ether and mg. of the saidproduct melting at 135 C. and 162 C. was recovered from the etherealphases. The two products were combined, dissolved in acetone, thesolution was treated with carbon blackalumina mixture and the productwas recrystallized from acetone-isopropyl ether mixture to obtain paleyellow prismatic crystals of 2-oxa-13,8-ethyl-17a-methyl-Agonatriene-17B-ol-3-one having melting points of 150 C. and 164 C. and aspecific rotation [a] =-46:2 (c.=0.7% in chloroform).

Analysis. C H O (molecular weight=300.38): Calculated (percent): C,75.97; H, 8.05. Found (percent): C, 76.0; H, 8.0.

UV spectrum A max. at 230 mn itm.=l86, e=5,580 A max. at 328-329 ma Asfar as is known, this compound is not described in the literature.

'PHARMACOLOGICAL DATA Androgenic and anabolic activity The tests wereeffected according to the Herschberger technique (Proc. Soc. Exp. Biol.Med., 1953, 83, 175) slightly modified. This consists of a dailyadministration Sunday, then sacrificed the eleventh day, 22 to 26 hoursafter the last administration. The animals were autopsied after thesacrifice and the organs of interest were separated and weighed, inparticular the lifter muscle of the anus (levator ani) in order to studythe myotrophic and anabolic action as well as the ventral prostate andthe seminal vesicles in order to study the simultaneous androgeniceffect. When administered subcutaneously, the products were dissolved inolive oil containing 5% benzyl alcohol and when administered orally, theproducts were dissolved in olive oil. The dosages were divided into 9administrations over 10 days. The results are reported in the followingtables.

TABLE I.-10 DAY ORAL ADMINISTRATION Fresh levator Seminal anl in,vesicles Prostate Lots Dosage mg. in, mg. in, mg.

Control 0 20. 6 5. 2 7. 0

2-oxa-13fl-ethyl-l7a-methyl-A gonatriene-17 S-ol-3-one 51 X10/9 34. 728. 6 47. 3 X10/9 42. 1 42. 1 61. 3 125 X10/9 58 2 78. 8 88. 0

17a-methyl-A -estratriene-17B-ol-3-one 10'yX10/9 32. 9 15. 4 29. 5'yX10/9 40. 0 50. 8 63. 2 250 X10/9 59 0 102. 9 94. 3

Cnnfml 0 24. 1 4. 8 8. 4

2-oxa-17a-methyl-A --"-estratriene-17flo1-3-one 107X10/9 50. 8 47. 7 71.2 1007X10/9 66. 4 136. 6 118. 3

17a-methy1-A -estratriene-l7B-ol-3-one 107X10/9 35. 4 17. 0 34. 2l00'yX10/9 63. 7 67. 6 94. 6

TABLE II.--7 DAY ORAL ADMINISTRATION Fresh levator Seminal ani in,vesicles Prostate Lots Dosage mg. in, mg. in, mg.

Control 0 13. 1 4. 8 9. 0

2-oxa-17a-methyl-A -estratriene-17fl- 27 25. 9 17. 6 29. 3 01-3-0118.107 39. 3 40. 6 55. 0 507 39. 2 64. 5 70. 8

17a-methy1-A -estratrlene-17fl-ol-3-one. 107 27. 9 18. 2 30. 8 507 32. 733. 0 58. 1 2507 32. 8 66. 5 77. 6

TABLE III.10 DAY SUBCUTANEOUS ADMINISTRATION Fresh levator Seminal anlin, vesicles Prostate Lots Dosage mg. in, mg. in, mg.

Control 0 18. 5 8. 2 14. 2

2-oxa-13B-ethyl-17a-methyl-A- --"-gona- 2 X10/9 33. 6 12. 7 16. 0tr1ene-17fl-ol-3-one. 107X10/9 47. 4 19. 2 23. 507X10/9 44. 5 37. 1 37.

17fi-acetoxy-A -estratrleue-3-one 10 x 10/9 36. 9 10. 8 11. 50 x 10/946. 4 21. 0 15 2507X 10/9 56. 1 51. 8 36.

Control 0 15. 4 4. 8 10.

2-oxa-l7a-methyl-A -estratrlene-Ufl- 107x 10 9 49. 8 42. 9 56.01-3-0116. 'yX 10 9 62. 5 145. 4 149.

17/9-acet0xy-A -estratriene-3-one 10 X10/9 37. 1 23. 4 26. 100yX10/9 55.5 76. 7 79.

Controls 0 21. 2 9. 8 12.

2-oxa-17a-methyl-A -estratrlene-17fl- 1'yX10/9 30. 8 10. 7 25. ol-3-one.101x 10/9 47. 3 50. 8 67.

17B-acetoxy-A -estratrlene-li-one 10'yX10/9 37. 4 22. 7 36. 100'yX10/953. 1 84. 6 77.

The above tables show that the compounds of the invention possessremarkable anabolic and androgenic activity. In the Hershberger test,2-oxa-17a-methyl-A estratriene-17p-ol-3-one is active at Drsubcutaneously and 2A orally, which is about 10 times the subcutaneousactivity of 17/3-acetoxy-A -estratriene 3 one and 5 times the oralactivity of 17a-methyl-A -estratrienel7 3-ol-3-one. The oral activity of2-0xa-13fl-ethyl-17amethyl-A -gonatriene-17fl-ol-3-one is about twicethat of 17a-methyl-A -estratriene-17 3-ol-3-one and its subcutaneousactivity is about 5 times that of 17fl-acetoxy- A -estratriene-3-one.

Various modifications of the compositions and method of the inventionmay be made without departing from the spirit or scope thereof.

vWe claim:

1. A compound having a formula selected from the group consisting of OHR 0H and HO-CH wherein R is selected from the group consisting of methyland ethyl.

2.. The compound of claim 1 wherein R is methyl. 3. The compound ofclaim 1 wherein R is ethyl.

References Cited UNITED STATES PATENTS 1/1967 Cross 260-586 H X 25HOWARD T. MARS, Primary Examiner G. A. SCHWARTZ, Assistant Examiner1233; UNITED STATES PATENT 0mm CERTIFICATE OF Patent No. 3,752,855 DanaAug. 1 5 973 ROBERT BUCOURT and LUCIEN NEDC Mouton-(sf it is:ert::l.f1'.ed that error appeare in the above ideneified patent thatsaid Letters Patent are hereby corrected as shown below:

rm u Q91. Line Page Line I I 7 27 1 12 "gas" should be gave 1O 16 6"326-427 mp" should be -=-326-327 m 10 33 21 26 "mole" should be--moles-- ll 8 23 ll "Herschber'ger' should be --Hershberger UNITEDSTATES PATENT owner Page 2 CERTIFICATE OF C6 EC'HQN Patent No. 3,752,855Dated August 11;, 1973 Inventor(s) ROBERT BUCOURT AND LUCIEN NEDELEC Itis certified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Patent A lm- Col. Line Page Line CLAIMS- Claim Signed and sealed this19th day of March 1971 (SEAL) Attest:

EDWARD M.FLETCHER,JR. C. MARSHALL DANN Attesting Officer Commissioner ofPatents FORM Po-mso (10-69) I USCOMM-DC scan-pea U,S. GOVERNMENTPRINTING OFFICE: IDD 0*366-354.

